Enhancing immune therapy in pancreatic cancer by targeting IL-6

通过靶向 IL-6 增强胰腺癌的免疫治疗

• 批准号: 10224899
• 负责人: Gregory B. Lesinski
• 金额: $ 30.36万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-12 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224899
• 关键词: Address; Antibodies; Cell Differentiation process; Cells; Clinical; Complement component C6; Data; Disease; Fibroblasts; Genetic Models; Granulocyte-Macrophage Colony-Stimulating Factor; Hormones; Human; Immune; Immune Evasion; Immune response; Immune system; Immunity; Immunologic Markers; Immunosuppression; Immunotherapy; In Vitro; Interleukin-6; Literature; Malignant neoplasm of pancreas; Mediating; Mus; Myeloid-derived suppressor cells; Myofibroblast; Neoplasm Metastasis; PD-L1 blockade; Paclitaxel; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Phenotype; Process; Property; Publications; Role; STAT3 gene; Shapes; Signal Transduction; Smooth Muscle Actin Staining Method; Source; Specimen; Stromal Cells; System; T-Lymphocyte; Therapeutic Effect; Tissues; Treatment Efficacy; Tumor-infiltrating immune cells; Work; base; carcinogenesis; cell type; chemotherapy; conditional knockout; gemcitabine; improved; in vivo; innovation; interest; loss of function; macrophage; mouse model; mutant; novel; pancreatic cancer cells; pancreatic cancer patients; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; pancreatic stellate cell; preclinical study; programmed cell death ligand 1; rapid testing; recombinase; response; subcutaneous; taxane; transcription factor; tumor; tumor growth; tumor microenvironment; tumor progression

Pancreatic ductal adenocarcinoma (PDAC) is accompanied by profound systemic immunosuppression that renders this disease non-responsive to immunotherapy. One hallmark of PDAC is the dense stroma consisting of activated fibroblasts termed `pancreatic stellate cells' (PSC) that surround each tumor. Although these stromal cells produce numerous factors that may support tumor growth, recent publications also suggest a contradictory role for the stroma in protecting against metastasis. Even more surprising was the observation that depletion of PSC from genetic models of PDAC led to improved efficacy of immunotherapy. These data highlight the significance of the proposal, and how little is known regarding the intricate interactions between stroma and immune cells present within the tumor microenvironment. These results also suggest that the immune response against tumors is restrained by PSC, and that targeting key pathways in the stroma may augment the efficacy of immunotherapy. In line with these observations, a recent publication from our group demonstrated that patient-derived PSC secrete soluble factors to promote myeloid-derived suppressor cell (MDSC) differentiation. Detailed analyses revealed that STAT3 signaling was required for this process, and was due to copious amounts of interleukin-6 (IL-6) secreted from PSC. These data demonstrated a novel role for stromal PSC as a source of factors that suppress immunity in PDAC, and have fueled our interest in targeting IL-6 to enhance immunotherapy. Our preliminary data show that in vivo administration of antibodies (Ab) targeting interleukin-6 (IL-6) and PD-L1 limit tumor progression in both subcutaneous, and autochthonous, mutant KRas-driven models of PDAC. We also demonstrate this treatment combination results in increased infiltration of T cells into pancreatic tumors, and reduced levels of PSC within these same tumors. We hypothesize that stromal IL-6 is a major barrier promoting immune suppression in PDAC, and that it can be targeted to augment the response to immunotherapy. This proposal will address three Specific Aims. First, we will determine the mechanisms by which combined blockade of IL-6 and PD-L1 elicits antitumor efficacy in PDAC, focusing on phenotypic and functional properties of T cells and MDSC (Aim 1). The relative importance of PD-L1 expression on the tumor or host tissues in mediating efficacy of this treatment will be investigated. Next, we will determine if taxane-based chemotherapy augments the efficacy of IL-6 and PD-L1 blockade in autochthonous, mutant KRas-driven PDAC models (Aim 2). Finally, we will use a dual recombinase system (Flp-FRT and Cre-loxP) to develop mice with spontaneously arising, mutant KRas-driven PDAC and IL-6 deleted fibroblasts, and primary patient PSC to define the role of stromal IL-6 in promoting pancreatic cancer progression and immune suppression (Aim 3). This proposal will enhance our understanding of how the stroma influences carcinogenesis and immune suppression in PDAC. Data from these studies also have potential for near-term clinical impact with Ab targeting IL-6 in combination with immunotherapy.

胰腺导管腺癌（PDAC）伴有严重的全身免疫抑制， 使这种疾病对免疫治疗无反应。 PDAC 的标志之一是由致密基质组成 每个肿瘤周围都有被称为“胰腺星状细胞”（PSC）的活化成纤维细胞。虽然这些 基质细胞产生许多可能支持肿瘤生长的因子，最近的出版物还表明 基质在防止转移方面的矛盾作用。更令人惊讶的是观察结果 从 PDAC 遗传模型中去除 PSC 可以提高免疫疗法的疗效。这些数据 强调该提案的重要性，以及人们对两者之间错综复杂的相互作用知之甚少。 基质和免疫细胞存在于肿瘤微环境中。这些结果还表明 针对肿瘤的免疫反应受到 PSC 的抑制，并且靶向基质中的关键途径可能 增强免疫治疗的疗效。根据这些观察，我们小组最近发表了一篇文章 证明患者来源的 PSC 分泌可溶性因子以促进骨髓来源的抑制细胞 （MDSC）分化。详细分析表明该过程需要 STAT3 信号传导，并且 这是由于 PSC 分泌大量白细胞介素 6 (IL-6)。这些数据展示了新的作用 间质 PSC 是抑制 PDAC 免疫的因素的来源，并激发了我们对 靶向IL-6以增强免疫治疗。我们的初步数据表明，抗体的体内施用 (Ab) 靶向白介素 6 (IL-6) 和 PD-L1 限制皮下和原地肿瘤进展， 突变 KRas 驱动的 PDAC 模型。我们还证明了这种治疗组合可以增加 T 细胞浸润到胰腺肿瘤中，并降低这些肿瘤内的 PSC 水平。我们 假设基质 IL-6 是促进 PDAC 免疫抑制的主要屏障，并且它 可以有针对性地增强对免疫疗法的反应。该提案将解决三个具体问题 目标。首先，我们将确定联合阻断 IL-6 和 PD-L1 引发抗肿瘤的机制 PDAC 的功效，重点关注 T 细胞和 MDSC 的表型和功能特性（目标 1）。亲戚 肿瘤或宿主组织上的 PD-L1 表达在调节这种治疗功效中的重要性将是 调查了。接下来，我们将确定基于紫杉烷的化疗是否可以增强 IL-6 和 PD-L1 的疗效 阻断本地突变 KRas 驱动的 PDAC 模型（目标 2）。最后，我们将使用双 重组酶系统（Flp-FRT 和 Cre-loxP）可培养具有自发产生的突变 KRas 驱动的小鼠 PDAC 和 IL-6 删除了成纤维细胞和原发性患者 PSC，以确定基质 IL-6 在促进 胰腺癌进展和免疫抑制（目标 3）。这个建议将加深我们的理解 研究基质如何影响 PDAC 的癌变和免疫抑制。这些研究的数据还 靶向 IL-6 的抗体与免疫疗法相结合，有可能产生近期临床影响。

项目成果

IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer.

• DOI: 10.1136/gutjnl-2016-311585
• 发表时间: 2018-02
• 期刊: Gut
• 影响因子: 24.5
• 作者: Mace TA;Shakya R;Pitarresi JR;Swanson B;McQuinn CW;Loftus S;Nordquist E;Cruz-Monserrate Z;Yu L;Young G;Zhong X;Zimmers TA;Ostrowski MC;Ludwig T;Bloomston M;Bekaii-Saab T;Lesinski GB
• 通讯作者: Lesinski GB